Rhodium-Catalyzed Addition ofArylboronic Acids to Isatins:An Entry to Diversity in3-Aryl-3-HydroxyoxindolesPatrick Y. Toullec, † Richard B. C. Jagt, † Johannes G. de Vries,* ,‡

Ben L. Feringa,* ,† and Adriaan J. Minnaard* ,†

Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute,UniVersity of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands, andDSM Research, Life SciencessAdVanced Synthesis & Catalysis, P.O. Box 18,6160 MD, Geleen, The Netherlands

a.j.minnaard@rug.nl; b.l.feringa@rug.nl; hans-jg.Vries-de@dsm.com

Received April 4, 2006

ABSTRACT

A general method for the catalytic 1,2-addition of aryl and alkenyl boronic acids to isatins is described using a rhodium(I)/triphenylphosphitecatalyst. The application of this transformation allows the synthesis of a variety of 3-aryl-3-hydroxyoxindole building blocks in high yields. Anenantioselective version of this reaction using a rhodium(I)/phosphoramidite system is also presented.

3-Substituted 3-hydroxyoxindoles are encountered in a largevariety of natural products with a wide spectrum of biologicalactivities, such as convolutamydines,1a donaxaridines,1b,c

maremycins,1d dioxibrassinines,1e celogentin K,1f 3′-hydroxyhydroxyglucoisatisins,1g and TMC-95A.1h Molecules that

include this structural unit constitute major targets in thedevelopment of drug candidates. 3-Alkenyl- and 3-aryl-substituted 3-hydroxyoxindoles,2 and derivatives thereof,3

have been used in a number of recent pharmaceutical studies.Biological activities were found to be extremely sensitiveto the substitution pattern of the aryl substituent as well asthe absolute configuration of the stereogenic center. Untilnow, no general synthetic procedure has been reported forthe preparation of this type of compound with a large varietyof aryl groups.4 Such a procedure, preferably in an enantio-selective fashion, would be essential for its biological

† University of Groningen.‡ DSM Research.(1) (a) Kamano, Y.; Zhang, H.-P.; Ichihara, Y.; Kizu, H.; Komiyama,

K.; Pettit, G. R.Tetrahedron Lett.1995, 36, 2783. (b) Rasmussen, H. B.;MacLeod, J. K.J. Nat. Prod.1997, 60, 1152. (c) Kawasaki, T.; Nagaoka,M.; Satoh, T.; Okamoto, A.; Ukon, R.; Ogawa, A.Tetrahedron2004, 60,3493. (d) Balk-Bindseil, W.; Helmke, E.; Weyland, H.; Laatsch, H.LiebigsAnn. 1995, 1291. (e) Monde, K.; Sasaki, K.; Shirata, A.; Tagusuki, M.Phytochemistry1991, 30, 2915. (f) Suzuki, H.; Morita, H.; Shiro, M.;Kobayashi, J.Tetrahedron2004, 60, 2489. (g) Fre´chard, A.; Fabre, N.;Pean, C.; Montaut, S.; Fauvel, M.-T.; Rollin, P.; Fouraste´, I. TetrahedronLett. 2001, 42, 9015. (h) Kohno, J.; Koguchi, Y.; Nishio, M.; Nakao, K.;Kuroda, M.; Shimizu, R.; Ohnuki, T.; Komatsubara, S.J. Org. Chem.2000,65, 990.

(2) (a) Hewawasam, P.; Meanwell, N. A.; Gribkoff, V. K.; Dworetzky,S. I.; Biossard, C. G.Bioorg. Med. Chem. Lett.1997, 7, 1255. (b)Hewawasam, P.; Erway, M.; Moon, S. L.; Knippe, J.; Weiner, H.; Biossard,C. G.; Post-Munson, D. J.; Gao, Q.; Huang, S.; Gribkoff, V. K.; Meanwell,N. A. J. Med. Chem.2002, 45, 1487.

ORGANICLETTERS

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10.1021/ol0608101 CCC: $33.50 © 2006 American Chemical SocietyPublished on Web 05/26/2006

evaluation by systematic structural variation in a libraryapproach.

There are a number of recent reports on the catalyticenantioselective formation of quaternary carbon centers atthe 3-position of oxindoles.5 However, the catalytic enanti-oselective formation of a tertiary alcohol at this position hasbeen elusive until now.6 The formation of quaternary carboncenters7 via addition of carbon nucleophiles to ketonederivatives still constitutes a major challenge for syntheticchemistry.8 Catalytic enantioselective synthesis ofR-hy-droxycarbonyl compounds via addition of organometallicnucleophiles toR-dicarbonyl substrates has so far beenlimited to alkynylations9 and alkylation reactions using zincreagents.10 Inspired by the progress in the field of rhodium-catalyzed additions of sp2-hybridized carbon nucleophiles toa variety of electrophiles,11,12 we decided to investigate the

arylation and alkenylation of isatin substrates using acombination of boronic acids13,14 and rhodium catalysts toachieve the synthesis of 3-substituted 3-hydroxyoxindoles.

Experiments conducted with isatin1a and 2 equiv ofphenylboronic acid2a in the presence of a catalyst generatedin situ from 3 mol % of [(C2H4)2Rh(acac)] and 7 mol % ofP(OPh)3 lead to full conversion and 91% isolated yield of3aafter 4 h atreflux temperature (Scheme 1). Although this

class of substrates represents highly activated carbonyl com-pounds, to the best of our knowledge, this is the first reportof rhodium-catalyzed arylboronic acid addition to ketones.6,15

This reaction was applied to isatin substrates1a-c and avariety of arylboronic acids2a-k (Table 1). As alreadyobserved by Frost for the addition of arylboronic acids to

(3) (a) Hewawasam, P.; Meanwell, N. A.; Gribkoff, V. K. U.S. Patent5,602,169,1997; Chem. Abstr.1997, 126, 181369. (b) Gribkoff, V. K.;Starrett, J. E., Jr.; Dworetzky, S. I.; Hewawasam, P.; Boissard, C. G.; Cook,D. A.; Frantz, S. W.; Heman, K.; Hibbard, J. R.; Huston, K.; Johnson, G.;Krishnan, B. S.; Kinney, G. G.; Lombardo, L. A.; Meanwell, N. A.;Molinoff, P. B.; Myers, R. A.; Moon, S. L.; Ortiz, A.; Pajor, L.; Pieschl,R. L.; Post-Munson, D. J.; Signor, L. J.; Srinivas, N.; Taber, M. T.; Thalody,G.; Trojnacki, J. T.; Weiner, H.; Yeleswaram, K.; Yeola, S. W.Nat. Med.2001, 7, 471. (c) Natarajan, A.; Fan, Y.-H.; Chen, H.; Guo, Y.; Iyasere, J.;Harbinski, F.; Christ, W. J.; Aktas, H.; Halperin, J. A.J. Med. Chem.2004,47, 1882. (d) Natarajan, A.; Guo, Y.; Harbinski, F.; Fan, Y.-H.; Chen, H.;Luus, L.; Diercks, J.; Aktas, H.; Chorev, M.; Halperin, J. A.J. Med. Chem.2004, 47, 4979. (e) Cliffe, I. A.; Lien, E. L.; Mansell, H. L.; Steiner, K. E.;Todd, R. S.; White, A. C.; Black, R. M.J. Med. Chem.1992, 35, 1169.

(4) The synthesis of enantiomerically enriched 3-aryl-3-hydroxyoxin-doles has been accomplished via the highly diastereoselective arylation ofmandelic acid: (a) Barroso, S.; Blay, G.; Cardona, L.; Ferna´ndez, I.; Garcı´a,B.; Pedro, J. R.J. Org. Chem.2004, 69, 6821. For the synthesis ofenantiomerically enriched 3-aryl-3-hydroxyoxindoles by asymmetric hy-droxylation using chiral oxaziridines, see ref 2b.

(5) Palladium-catalyzed intramolecularR-arylation: (a) Lee, S.; Hartwig,J. F. J. Org. Chem.2001, 66, 3402. Intramolecular Heck reaction: (b)Dounay, A. B.; Hatanaka, K.; Kodanko, J. J.; Oestreich, M.; Overman, L.E.; Pfeifer, L. A.; Weiss, M. M.J. Am. Chem. Soc.2003, 125, 6261.Organocatalytic acyl transfer: (c) Hills, I. D.; Fu, G. C.Angew. Chem.,Int. Ed. 2003, 42, 3921. Biocatalytic desymmetrization of prochiralsubstrates: (d) Akai, S.; Tsujino, T.; Akiyama, E.; Tanimoto, K.; Naka,T.; Kita, Y. J. Org. Chem.2004, 69, 2478. Lewis-catalyzedR-fluorinationof carbonyl groups: (e) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura,Y.; Sodeoka, M.J. Am. Chem. Soc.2005, 127, 10164. Palladium-catalyzedallylation of prochiral nucleophiles: (f) Trost, B. M.; Frederiksen, M. U.Angew. Chem., Int. Ed.2005, 44, 308. Organocatalytic aldol reaction: (g)Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.; Broxterman, Q. B.;Tomasini, C.J. Org. Chem.2005, 70, 7418.

(6) After submission of this manuscript, the group of Hayashi reportedthe rhodium-catalyzed asymmetric addition of aryl- and alkenylboronic acidsto isatins: Shintani, R.; Inoue, M.; Hayashi, T.Angew. Chem., Int. Ed.2006, 45, 3353.

(7) For reviews on the formation of quaternary carbon centers, see: (a)Corey, E. J.; Guzman-Perez, A.Angew. Chem., Int. Ed.1998, 37, 388. (b)Denissova, I.; Barriault, L.Tetrahedron2003, 59, 10105. (c) Ramo´n, D.J.; Yus, M.Curr. Org. Chem.2004, 8, 149. (d) Christoffers, J.; Baro, A.AdV. Synth. Catal.2005, 247, 1473. (e) Trost, B. M.; Jiang, C.Synthesis2006, 369. (f) Christoffers, J., Baro, A., Eds.Quaternary Stereocenters:Challenges and Solutions for Organic Synthesis; Wiley-VCH: Weinheim,Germany, 2005.

(8) For a recent review on enantioselective addition to ketones usingzinc reagents, see: (a) Ramo´n, D. J.; Yus, M.Angew. Chem., Int. Ed. 2004,43, 284. For leading references in the field of catalytic enantioselectiveadditions of organometallic aryl and alkenyl reagents to carbonyl com-pounds, see: (b) Garcı´a, C.; Walsh, P. J.Org. Lett. 2003, 5, 3641. (c) Li,H.; Walsh, P. J.J. Am. Chem. Soc. 2005, 127, 8355. (d) Tomita, D.; Wada,R.; Kanai, M.; Shibasaki, M.J. Am. Chem. Soc. 2005, 127, 4138.

(9) (a) Jiang, B.; Chen, Z.; Tang, X.Org. Lett. 2002, 4, 3451. (b) Dhondi,P. K.; Chisholm, J. D.Org. Lett.2006, 8, 67.

(10) (a) DiMauro, E. F.; Kozlowski, M. C.J. Am. Chem. Soc. 2002,124, 12668. (b) DiMauro, E. F.; Kozlowski, M. C.Org. Lett. 2002, 4, 3781.(c) Funabashi, K.; Jachmann, M.; Kanai, M.; Shibasaki, M.Angew. Chem.,Int. Ed. 2003, 42, 5489.

Scheme 1. Rhodium/Triphenylphosphite-Catalyzed Additionof Arylboronic Acids to Isatin

Table 1. Rhodium/Triphenylphosphite-Catalyzed 1,2-Additionof Aryl- and Alkenylboronic Acids to Isatins

entrya isatin (R1) boronic acid product yieldb

1 1a (H) 2a 3a 91%2 1b (Me) 2a 3b 79%3 1c (Cl) 2a 3c 99%4 1a (H) 2b 3d 99%5 1a (H) 2c 3e 99%6 1a (H) 2d 3f 99%7 1a (H) 2e 3g 98%8 1a (H) 2f 3h 87%9 1a (H) 2g 3i 66%

10 1c (Cl) 2h 3j 62%11 1a (H) 2i 3k 43%12 1a (H) 2j 3l 54%13 1a (H) 2k 3m 96%

a All reactions were performed on 0.2 mmol scale in 2 mL of acetone atreflux for 4 h with 2 equiv of arylboronic acid (2) in the presence of acatalyst generatedin situ from 3 mol % of [(C2H4)2Rh(acac)] and 7 mol %of triphenylphosphite.b Isolated yields of3 after column chromatography.

2716 Org. Lett., Vol. 8, No. 13, 2006

aldehydes,16 this 1,2-addition reaction is influenced by theelectronic substitution pattern of both reaction partners.Electron-donating groups on the isatin substrate lower thereactivity (entry 2), while electron-withdrawing substituentscause an increase of reactivity (entry 3). Electron-donatingsubstituents on the boronic acid result in high yields (entries4-8), while electron-withdrawing ones lead to moderatevalues (entries 9-11). Steric hindrance of the boronic aciddoes not influence the yield (compare entries 4-6). Phenylgroups with electrophilic substituents, which are generallynot tolerated by organomagnesium or organolithium reagents,were introduced here with success (entries 9-11).14 Alsoortho-fluorophenyl, for which the Grignard reagent is notavailable, was successfully introduced (entry 11). An ad-ditional advantage of the present strategy is the fact that itproceeds without protecting the amide functionality of thesubstrate.

In contrast with the initial report of Miyaura on therhodium-catalyzed arylboronic acid addition to aldehydes,17

our system does not require the presence of any added proticsource.18 Although the substrate is protic itself, similarobservations using aldehydes as substrates seem to indicatethat the alkoxy speciesC (Scheme 2) resulting from the

arylation of the carbonyl function is acting as a nucleophilein the transmetalation step to regenerate the catalytic activeintermediateA.12d

In relation with previous studies12d,econducted in our groupon asymmetric 1,2-arylations using substrates with carbon-heteroatom double bonds, we investigated an array of binol-based phosphoramidite ligands,19 a class of cheap, easilyprepared ligands, successful in the rhodium-catalyzed con-jugate addition of arylboronic acids to enones.12a-c This ledto the discovery of moderate enantioselectivities using thenew phosphoramidite ligandL (Scheme 3).

In preliminary experiments, a series of chiral phosphora-midite ligands was tested with model substrate1a andphenylboronic acid2a. In the presence of a catalyst generatedfrom 3 mol % of [(C2H4)2Rh(acac)] and 9 mol % of ligandL ,20 3-phenyl-3-hydroxyoxindole (3a) was obtained in virtu-ally quantitative yield and 55% ee.21 Upon recrystallizationfrom 2-propanol, the supernatant gave the enantioenrichedproduct in 59% yield and 94% ee.

In conclusion, we have discovered the 1,2-addition ofarylboronic acids to isatin substrates based on a combinationof a rhodium(I) precursor and 2 equiv of triphenylphosphite.This method represents a general procedure for the formationof 3-aryl-3-hydroxyoxindoles in good to excellent yields.Promising enantioselectivities are obtained in an asymmetricversion of this reaction employing a phosphoramidite ligand.Further studies to expand this methodology to other classesof substrates and to improve the enantioselectivity of theasymmetric addition are currently in progress.

(11) For reviews on this topic, see: (a) Hayashi, T.Synlett2001, 879.(b) Hayashi, T.; Yamasaki, K.Chem. ReV. 2003, 103, 2829. (c) Fagnou,K.; Lautens, M.Chem. ReV. 2003, 103, 169.

(12) (a) Boiteau, J.-G.; Imbos, R.; Minnaard, A. J.; Feringa, B. L.Org.Lett. 2003, 5, 681;Org. Lett.2003, 5, 1385. (b) Boiteau, J.-G.; Minnaard,A. J.; Feringa, B. L.J. Org. Chem.2003, 68, 9481. (c) Duursma, A.; Hoen,R.; Schuppan, J.; Hulst, R.; Minnaard, A. J.; Feringa, B. L.Org. Lett.2003,5, 3111. (d) Jagt, R. B. C.; Toullec, P. Y.; de Vries, J. G.; Feringa, B. L.;Minnaard, A. J.Org. Biomol. Chem.2006, 4, 773. (e) Jagt, R. B. C.; Toullec,P. Y.; Geerdink, D.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J.Angew.Chem., Int. Ed.2006, 45, 2789.

(13) (a) Miyaura, N.; Suzuki, A.Chem. ReV. 1995, 95, 2457. (b) Hall,D. G., Ed. Boronic Acids: Preparation and Applications in OrganicSynthesis and Medicine; Wiley-VCH: Weinheim, Germany, 2005.

(14) For a discussion of the advantages of arylboronic acids in 1,2-addition reactions regarding functional group tolerance, see: Fu¨rstner, A.;Krause, H.AdV. Synth. Catal.2001, 343, 343.

(15) For the asymmetric addition of arylzinc reagents, generated in situfrom arylboronic acids and diethylzinc to acetophenones, see: (a) Prieto,O.; Ramon, D. J.; Yus, M.Tetrahedron: Asymmetry2003, 14, 1955. Alsosee: (b) Bolm, C.; Rudolph, J.J. Am. Chem. Soc.2002, 124, 14850.

(16) Moreau, C.; Hague, C.; Weller, A. S.; Frost, C. G.TetrahedronLett. 2001, 42, 6957.

(17) Sakai, M.; Ueda, M.; Miyaura, N.Angew. Chem., Int. Ed.1998,37, 3279.

(18) For a comprehensive mechanistic rationale of the rhodium-catalyzedarylboronic acid conjugate addition to enones and a discussion of the crucialrole of the protic source in the catalytic activity, see: Hayashi, T.; Takahashi,M.; Takaya, Y.; Ogasawara, M.J. Am. Chem. Soc.2002, 124, 5052.

(19) Feringa, B. L.Acc. Chem. Res.2000, 33, 346.(20) A ligand/rhodium ratio of 3/1 gave the optimum enantioselectivity.

Using a lower ratio, the ee decreases slightly. This is probably due tocompetitive chelating properties of both substrate1 and product3. Usinga higher ratio, dramatically lower activity was observed.

(21) Ligand (S)-L provided product (S)-3a. For determination of theabsolute configuration of compound3a, see: Barroso, S.; Blay, G.; Cardona,L.; Fernandez, I.; Garcia, B.; Pedro, J. R.J. Org. Chem.2004, 69, 6821and the discussion in the Supporting Information.

Scheme 2. Proposed Mechanism of the Rhodium-Catalyzed1,2-Addition of Arylboronic Acids

Scheme 3. Enantioselective Rhodium/Phosphoramidite-Catalyzed 1,2-Addition of Arylboronic Acid to

Isatin

Org. Lett., Vol. 8, No. 13, 2006 2717

Acknowledgment. We thank Mrs. T. D. Tiemersma-Wegman and Mr. E. P. Schudde for their technical assistance.Dr. A. H. M. de Vries (DSM) is kindly acknowledged foruseful discussions. Financial support from DSM, the Ministryof Economic Affairs, and NWO/CW, administered throughthe CW/Combichem program, is gratefully acknowledged.

Supporting Information Available: Experimental de-tails, chromatographic, and spectroscopic data. This materialis available free of charge via the Internet at http://pubs.acs.org.

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